Pitt–Hopkins syndrome

Pitt–Hopkins syndrome
Classification and external resources
OMIM	610954

Pitt–Hopkins syndrome is a genetic disorder characterized by developmental delay, a wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea.^[1] It is associated with an abnormality within chromosome 18: specifically, it is caused by an insufficient expression of the TCF4 gene.^[2]

Genetics

The condition was first described in 1978 by Pitt and Hopkins in two unrelated patients.^[3]

The genetic cause of this disorder was described in 2007.^[4] This disorder is due to a haploinsufficiency of the transcription factor 4 (TCF4) gene which is located on the long arm of chromosome 18 (18q21.2) The mutational spectrum appears to be 40% point mutations, 30% small deletions/insertions and 30% deletions. All appear to be de novo mutations and to date no risk factors have been identified.

A Pitt–Hopkins like phenotype has been assigned to autosomal recessive mutations of the contactin associated protein like 2 (CNTNAP2) gene on the long arm of chromosome 7 (7q33-q36) and the neurexin 1 alpha (NRXN1) gene on the short arm of chromosome 2 (2p16.3).^[5]

Clinical

Approximately 100 cases have been described in the literature to date.

The facial features are characteristic and include

Deep set eyes
Strabismus
Myopia
Marked nasal root
Broad and/or beaked nasal bridge
Prominent Cupid's bow
Everted lower lip
Tented upper lip
Large mouth
Widely spaced teeth
Wide and shallow palate
Ears with thick and overfolded helix

Most have a smiling appearance

Intellectual disability is severe. Language is absent or limited to only a few words. Stereotypic movements particularly of the arms, wrists and fingers is almost universal. Hypotonia is common (75%) as is an unsteady gait. All have delayed walking. Other features include a single (simian) palmar crease, long, slender fingers, flat feet and cryptorchidism (in males). Finger clubbing and the presence of fetal pads is common. Hyperventilation occurs in over half and is frequently followed by apnea and cyanosis. During these episodes aerophagia may occur. Constipation is common. Microcephaly and seizures may occur. Hypopigmented skin macules have occasionally been reported.

Investigations

~50% show abnormalities on brain imaging. These include hypoplastic corpus callosum with a missing rostrum and posterior part of the splenium with bulbous caudate nuclei bulging towards the frontal horns.

Electroencephalograms show an excess of slow components.

All have low levels of immunoglobulin M (IgM) but features of an immunodeficiency are absent.

Differential diagnosis

This includes Angelman syndrome, Mowat–Wilson syndrome and Rett syndrome.

Diagnosis

This is made by showing a mutation in the TCF4 gene.

Treatment

Currently there is no specific treatment for this condition. Management is supportive.

Miscellaneous

Peter the Wild Boy, showing some of the physical traits of Pitt–Hopkins syndrome, including coarse, curly hair, drooping eyelids and large, thick lipped mouth.

Professor Phillip Beales, of the Institute of Child Health, has speculated that Peter the Wild Boy suffered from Pitt–Hopkins syndrome.^[6] The boy was brought to Britain in 1725 as a feral child.

References

↑ Zweier C, Peippo MM, Hoyer J et al. (May 2007). "Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome)". American Journal of Human Genetics 80 (5): 994–1001. doi:10.1086/515583. PMC 1852727. PMID 17436255.
↑ "PITT-HOPKINS SYNDROME; PTHS". National Center for Biotechnology Information. Retrieved 2009-12-08.
↑ Pitt D, Hopkins I (1978) A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paed J 14(3):182-184
↑ Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L (2007) Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am. J. Hum. Genet. 80: 988-993
↑ Peippo M, Ignatius J (2012) Pitt-Hopkins Syndrome. Mol Syndromol 2(3-5):171-180
↑ Megan Lane (8 August 2011). "Who was Peter the Wild Boy?". BBC News Magazine. BBC. Retrieved 2011-08-09.

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome

1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis

2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome

2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2

2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome

3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3

3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX

3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome

4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome

4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome

4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

Index of genetics

Description	Gene expression DNA replication cycle recombination repair binding proteins Transcription factors regulators nucleic acids RNA RNA binding proteins ribonucleoproteins repeated sequence modification Translation ribosome modification nexins Proteins domains Structure primary secondary tertiary quaternary

Disease	Replication and repair Transcription factor Transcription Translation